Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property
Guy A. Higgins, Nicole K. Carroll, Matthew A. Brown, Cam Macmillan, Leo B. Silenieks, Sandy Thevarkunnel, Julia Izhakova, Lilia Magomedova, Inés Delannoy, Edward M. Sellers
Frontiers in Pharmacology February 26, 2021 DOI: 10.3389/fphar.2021.640241 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Low performing male Long Evans rats |
| Interventions | Ketamine Psilocybin |
| Dose | ketamine 1–3 mg/kg IP; psilocybin 0.05–0.1 mg/kg SC |
| Topics | Ketamine Psilocybin Serotonin Esketamine |
| Keywords | Hallucinogen Anhedonia Dissociative Antidepressant Mood Pharmacology |
| Citations | 67 |
| Key findings | Low doses of ketamine and psilocybin produced modest improvements in motivation and attention in low-performing male rats, with similar effects across both drugs. |
Abstract
Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as “micro” doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3–3 mg/kg [10–73 ng/ml]) and psilocybin/psilocin (0.05–0.1 mg/kg [7–12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1–3 mg/kg IP) and psilocybin (0.05–0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as “low performing”. Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 62
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- A systematic literature review of clinical trials and therapeutic applications of ibogaine. Journal of Substance Abuse Treatment July 1, 2022
- Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective Frontiers in Psychiatry December 17, 2021
- Psilocybin in neuropsychiatry: a review of its pharmacology, safety, and efficacy CNS Spectrums July 11, 2022
- A journey with psychedelic mushrooms: From historical relevance to biology, cultivation, medicinal uses, biotechnology, and beyond Biotechnology Advances August 31, 2023
and 57 more in the library
Cites 31
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
and 26 more in the library